SLIT2

From Longevity Wiki

SLIT2 (Slit Guidance Ligand 2) is a protein coding gene that encode large secreted protein functioning as ligand for Roundabout (Robo) receptors.[1][2] The cleaved N-terminal fragment of SLIT2, N-SLIT2, acts via its receptor, Roundabout guidance receptor 1 (ROBO1), to attenuate inflammasome activation in macrophages by inhibiting macropinocytosis.[3] The SLIT family of genes consists of large extracellular matrix-secreted and membrane-associated glycoproteins.[4][5][6] SLIT2 is located in chromosome 4p15.2 and encodes the human orthologue of the Drosophila Slit-2 protein.[7] Slit was identified in Drosophila embryo as a gene involved in the patterning of larval cuticle. It was later shown that Slit is synthesized in the fly central nervous system by midline glia cells. Slit homologues have since been found in many vertebrate species, from amphibians, fishes, birds to mammals. There are three slit genes (slit1-slit3) in mammals, that have around 60% homology. All encodes large Extracellular matrix glycoproteins of about 200 kDa, comprising, from their N terminus to their C terminus, a long stretch of four leucine rich repeats (LRR) connected by disulphide bonds, seven to nine EGF (epidermal growth factor-like domain) repeats, laminin G-like module - a domain, named ALPS (Agrin, Perlecan, Laminin, Slit), and a cystein knot.[8] In vivo, Slit2 is cleaved into 140 kDa N-terminal (Slit2-N) and 55–60 kDa C-terminal (Slit2-C) fragments. Among them only recombinant Slit2-N showed a similar activity in stimulating branching and extension of dorsal root ganglia axons as reported for native Slit2-N purified from cells expressing wild-type full-length Slit2.[9]

SLIT family is involved in the epithelial-mesenchymal transition process that permits cancer cells to acquire migratory, invasive, and stem-like properties.[10] SLIT2 appears to function as a tumor suppressor gene. In addition, hypermethylation of its promoter region has been detected in various cancers, including breast and lung cancer, colorectal carcinoma, and gliomas.[11]


[12] [13] [14] [15]

SLIT2 progressively decreases as cells become senescent.[16] Treatment with recombinant human SLIT2 protein (rhSLIT2) resulted in decreased expression of inflammatory genes and proteins. In particular long-term treatment with rhSLIT2 protein resulted in upregulated expression of SOX2 and OCT4 and restored the morphology of mid-old (but not in old) fibroblasts, causing them to revert to a small and spindle-shaped morphology reminiscent of young cells. The proliferative capacity of such mid-old fibroblasts was recovered, accompanied by decreased levels of p21Waf1 mRNA and protein in a p53-independent manner.[16]

In the animal experiments with 23-month-old male mice treated by rmSLIT2 10 times over a duration of several weeks, mouse aging-related characteristics significantly improved. Specifically, activity in the cage and hanging ability increased. However, blood analysis showed no significant difference between the control and rmSLIT2-treated groups.[16] Surprisingly, SLIT2 decreased inflammatory response and improved proliferative capacity only in mid-old, but not in old fibroblasts.[16]

[17] [18]

During infection, Mycobacterium tuberculosis (Mtb) rewires distinct host signaling pathways that results in pathogen-favorable outcomes. In particular induced expression of the neuronal ligand SLIT2 which was due to the Mtb-mediated phosphorylation of the P38/JNK pathways. Activation of these kinases resulted in the loss of the repressive H3K27me3 signature on the Slit2 promoter.[19] I noticed that many centenarians came from families where the incidence of tuberculosis was high (for example Jeanne Calment). This allows me to assume as a working hypothesis that perhaps activation of the Slit2 gene by Mtb is involved in their longevity.

References

  1. ↑ Blockus, H., & Chédotal, A. (2016). Slit-robo signaling. Development, 143(17), 3037-3044. PMID: 27578174 DOI: 10.1242/dev.132829
  2. ↑ Wu, M. F., Liao, C. Y., Wang, L. Y., & Chang, J. T. (2017). The role of Slit-Robo signaling in the regulation of tissue barriers. Tissue Barriers, 5(2), e1331155. PMID: 28598714 PMCID: PMC5501134 DOI: 10.1080/21688370.2017.1331155
  3. ↑ Bhosle, V. K., Mukherjee, T., Huang, Y. W., Patel, S., Pang, B. W., Liu, G. Y., ... & Robinson, L. A. (2020). SLIT2/ROBO1-signaling inhibits macropinocytosis by opposing cortical cytoskeletal remodeling. Nature communications, 11(1), 4112. PMID: 32807784 PMC7431850 DOI: 10.1038/s41467-020-17651-1
  4. ↑ Little, M., Rumballe, B., Georgas, K., Yamada, T., & Teasdale, R. D. (2004). Conserved modularity and potential for alternate splicing in mouse and human Slit genes. International Journal of Developmental Biology, 46(4), 385-391.
  5. ↑ Piper, M., & Little, M. (2003). Movement through Slits: cellular migration via the Slit family. Bioessays, 25(1), 32-38. PMID: 12508280 DOI: 10.1002/bies.10199
  6. ↑ Wong, K., Park, H. T., Wu, J. Y., & Rao, Y. (2002). Slit proteins: molecular guidance cues for cells ranging from neurons to leukocytes. Current opinion in genetics & development, 12(5), 583-591. PMID: 12200164 DOI: 10.1016/s0959-437x(02)00343-x
  7. ↑ Georgas, K., Burridge, L., Smith, K., & Holmes, G. P. (1999). Assignment of the human slit homologue SLIT2 to human chromosome band 4p15. 2. Cytogenetic and Genome Research, 86(3/4), 246. PMID: 10575218 DOI: 10.1159/000015351
  8. ↑ Morlot, C., Thielens, N. M., Ravelli, R. B., Hemrika, W., Romijn, R. A., Gros, P., ... & McCarthy, A. A. (2007). Structural insights into the Slit-Robo complex. Proceedings of the National Academy of Sciences, 104(38), 14923-14928. PMID: 17848514 PMCID: PMC1975871 DOI: 10.1073/pnas.0705310104
  9. ↑ Ba-Charvet, K. T. N., Brose, K., Ma, L., Wang, K. H., Marillat, V., Sotelo, C., ... & Chédotal, A. (2001). Diversity and specificity of actions of Slit2 proteolytic fragments in axon guidance. Journal of Neuroscience, 21(12), 4281-4289. PMID: 11404413 PMC6762758 DOI: 10.1523/JNEUROSCI.21-12-04281.2001
  10. ↑ Basha, S., Jin-Smith, B., Sun, C., & Pi, L. (2023). The SLIT/ROBO Pathway in Liver Fibrosis and Cancer. Biomolecules, 13(5), 785. PMID: 37238655 PMCID: PMC10216401 DOI: 10.3390/biom13050785
  11. ↑ Jin, J., You, H., Yu, B., Deng, Y., Tang, N., Yao, G., ... & Qin, W. (2009). Epigenetic inactivation of SLIT2 in human hepatocellular carcinomas. Biochemical and Biophysical Research Communications, 379(1), 86-91. PMID: 19100240 DOI: 10.1016/j.bbrc.2008.12.022
  12. ↑ Dallol, A., Da Silva, N. F., Viacava, P., Minna, J. D., Bieche, I., Maher, E. R., & Latif, F. (2002). SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers. Cancer research, 62(20), 5874-5880. PMID: 12384551
  13. ↑ Liu, J. W., Liu, H. T., & Chen, L. (2021). The therapeutic role of Slit2 in anti-fibrosis, anti-inflammation and anti-oxidative stress in rats with coronary heart disease. Cardiovascular Toxicology, 21(12), 973-983. PMID: 34410632 DOI: 10.1007/s12012-021-09688-5
  14. ↑ Li, Q., Huang, L., Ding, Y., Sherchan, P., Peng, W., & Zhang, J. H. (2023). Recombinant Slit2 suppresses neuroinflammation and Cdc42-mediated brain infiltration of peripheral immune cells via Robo1–srGAP1 pathway in a rat model of germinal matrix hemorrhage. Journal of Neuroinflammation, 20(1), 249. PMID: 37899442 PMCID: PMC10613398 DOI: 10.1186/s12974-023-02935-2
  15. ↑ Li, X., Zheng, S., Tan, W., Chen, H., Li, X., Wu, J., ... & Yang, F. H. (2020). Slit2 protects hearts against ischemia-reperfusion injury by inhibiting inflammatory responses and maintaining myofilament contractile properties. Frontiers in physiology, 11, 228. PMID: 32292352 PMCID: PMC7135862 DOI: 10.3389/fphys.2020.00228
  16. ↑ 16.0 16.1 16.2 16.3 Kim, Y. H., Lee, Y. K., Park, S. S., Park, S. H., Eom, S. Y., Lee, Y. S., ... & Park, T. J. (2023). Mid-old cells are a potential target for anti-aging interventions in the elderly. Nature Communications, 14(1), 7619. DOI: 10.1038/s41467-023-43491-w
  17. ↑ Zhao, H., Anand, A. R., & Ganju, R. K. (2014). Slit2–Robo4 pathway modulates lipopolysaccharide-induced endothelial inflammation and its expression is dysregulated during endotoxemia. The Journal of Immunology, 192(1), 385-393. PMID: 24272999 PMC3908786 DOI: 10.4049/jimmunol.1302021
  18. ↑ Jones, C. A., Nishiya, N., London, N. R., Zhu, W., Sorensen, L. K., Chan, A. C., ... & Li, D. Y. (2009). Slit2–Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nature cell biology, 11(11), 1325-1331. PMID: 19855388 PMC2854659 DOI: 10.1038/ncb1976
  19. ↑ Borbora, S. M., Satish, B. A., Sundar, S., Bhatt, S., & Balaji, K. N. (2023). Mycobacterium tuberculosis elevates SLIT2 expression within the host and contributes to oxidative stress responses during infection. The Journal of Infectious Diseases, jiad126. PMID: 37158474 [https://doi.org/10.1093/infdis/jiad126 DOI: 10.1093/infdis/jiad126
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